What Are BRCA1 and BRCA2 Mutations? How Should Risk Be Managed for Carriers?

What Are the Functions and Mutations of the BRCA1 and BRCA2 Genes?

The name BRCA1 means "BReast CAncer 1 (Breast Cancer 1)", and the name BRCA2 means "BReast CAncer 2 (Breast Cancer 2)". The BRCA1 and BRCA2 genes, located on chromosome 17, play a role in cell growth, cell division, and DNA damage repair. In the BRCA genes, mutations can cause DNA damage to accumulate in cells without being repaired, which increases a person's likelihood of developing certain types of cancer.

Breast and ovarian (female ovary) cancer are the most common diseases linked to BRCA1 and BRCA2 gene changes, but mutated forms of the BRCA genes can also increase people's risk of other cancers. For example, men with a BRCA2 mutation have a higher risk of prostate cancer.

In general, people with BRCA mutations are at risk of

• developing cancer at an early age,
• developing cancer in both breasts, or
• developing more than one type of cancer during their lifetime.

For people with no personal or family history of breast or ovarian cancer, the likelihood of carrying a BRCA mutation is very low.

What Is the Risk of Having an Inherited BRCA Mutation?

Everyone has two copies of the BRCA1 and BRCA2 genes, and both men and women can pass on mutations in these genes.

If one of your two parents has a BRCA1 or BRCA2 mutation, you have a chance of inheriting the mutated (nonworking) BRCA gene from that parent. Your chance of inheriting the nonworking BRCA gene is 50 percent, which increases your cancer risk. You also have a 50 percent chance of inheriting a working BRCA gene, in which case you have the same cancer risk as someone in the general population.

Population Groups With an Increased Risk of Breast and Ovarian (Female Ovary) Cancer

Mutations in the BRCA genes have been found in people all over the world. However, these gene changes are more common in some groups, including Eastern European Jews known as Ashkenazi Jews and people from Iceland, Denmark, and French Canada.

• Related topic: Why Is Hereditary Breast Cancer So Common Among Ashkenazi Jews?

Three BRCA mutations, 185delAG, 6174delT, and 5382insC, are particularly common among Ashkenazi Jewish families, in which one in 40 people carries at least one of the mutations.

Women with these mutations have a higher risk of developing breast and ovarian cancer. Approximately 25 percent of Jewish women who develop breast cancer by age 41 have one of these BRCA mutations. People of Ashkenazi Jewish ancestry may have BRCA changes other than those mentioned here, but such BRCA changes do not occur often.

What Is the Risk of Ovarian Cancer in Women Who Have a Family History of Breast Cancer but Test Negative for BRCA?

A study reviewing cancer incidence in 165 families with three or more cases of breast cancer in their family tree but no BRCA1 or BRCA2 mutation showed an increased risk of breast cancer, but not ovarian cancer, among women in these families. The findings support the hypothesis that most ovarian cancers occurring in the same family as breast cancer are linked to BRCA1 and BRCA2.

Which Cancers Are Associated With BRCA1 Gene Mutations?

• On average, women with a mutant BRCA1 gene have a 50 to 85 percent risk of developing breast cancer by age 70. The risk of developing ovarian cancer is 40 to 60 percent by age 85.
• A woman with cancer in one breast has a higher risk of developing cancer in the other breast. Among those with the mutation, 25 to 30 percent may develop a second breast cancer within ten years of their first breast cancer.
• In both men and women, BRCA1 changes also increase the risk of some other cancers. People with a BRCA1 mutation may develop one or more cancers or may never be diagnosed with cancer.

Which Cancers Are Associated With BRCA2 Gene Mutations?

• Both men and women with a change in the BRCA2 gene have an increased risk of breast cancer. In women, the risks associated with a BRCA2 mutation appear to be about the same as those for BRCA1 mutations, with a 50 to 85 percent risk of developing the disease by age 70. Ovarian cancer risk is also increased, ranging from 16 to 27 percent later in life.
• A man with a BRCA2 change also has an increased risk of breast cancer. In addition, men with a mutation in BRCA2 have a higher risk of prostate cancer.
• Men and women with BRCA2 changes also have an increased risk of pancreatic cancer and melanoma.

RELATED TOPICS

Who Should Have Genetic Testing for Hereditary Breast Cancer?

Who Should Have Genetic Testing for Hereditary Ovarian Cancer?

BRCA Gene Variants (Changes)

DNA is made up of four chemical compounds called A (adenine), T (thymine), C (cytosine), and G (guanine), arranged in a specific order; in genetics, these are called bases. In many genes, the sequence or order of bases can differ between people. Such variations are usually harmless, but there are cases in which individual misspellings of bases or an incorrect order can cause disease. We are still learning which spellings are "normal" or harmless variants.

If you have something called a variant of uncertain significance (Variant of Uncertain Significance = VUS)* in one of your BRCA genes, you can have laboratory tests to find out whether the variant changes your cancer risk. However, there are times when we cannot tell whether a variant will increase your risk. If you have a variant, recommendations based on your family history may be made for cancer screening, and you can also have your relatives tested for this variant.

* Variant of Uncertain Significance (VUS): Sometimes a genetic test finds a change in BRCA1 or BRCA2 that has not previously been associated with cancer and is rare in the general population. This type of test result is called a "variant of uncertain significance," or VUS, because it is not known whether this specific genetic change is harmful.

Genetic counseling can help a person understand what a VUS in BRCA1 or BRCA2 means for cancer risk. Until the interpretation of the variant becomes clear, risk management should be based on family history and other risk factors. However, it is important for a person with a VUS test result to regularly obtain updated information from the test provider in case the VUS is reclassified as a harmful or likely harmful variant. Test providers have different policies for notifying a tested person of a change in the interpretation of a VUS test result. Some contact the tested person directly, while others place the responsibility on the tested person to check regularly for updates on the interpretation of VUS test results.

• Related topic: INHERITED Mutations Cause 1 in Every 8 Cancers – Should All Patients Be Tested?

Genetic Testing for Hereditary Breast and Ovarian Cancer

To find out whether a person has inherited a mutation in BRCA1 or BRCA2, a range of genetic tests is available.

If more than one family member is interested in being tested, it is best to start BRCA testing with a person who has (or previously had) breast or ovarian cancer.

If a DNA change is found, other family members can be tested only for the same mutation. Testing for BRCA mutations in stored DNA samples from deceased relatives is also possible.

Negative results (meaning no BRCA1 or BRCA2 change was found) may indicate one of the following:

• There is a BRCA1 or BRCA2 mutation that cannot be detected by the testing method used. No test can find all BRCA mutations.
• The cancers occurring in the family may have been caused by an inherited cancer gene mutation other than BRCA. For this reason, today, when a hereditary cancer is suspected, rather than testing only the BRCAs, multigene panel genetic tests are recommended.
• The breast or ovarian cancers in the family may have occurred sporadically / by chance. Because breast cancer is common, more than one woman in a particular family may develop breast cancer for reasons unrelated to inheritance.
• Sometimes a person may choose to test for only a particular mutation in the BRCA genes (for example, 185delAG). If the mutation is not found, there may still be a mutation in the BRCA genes for which the individual has not been tested.
• Finally, if someone with a known BRCA mutation in their family is tested and receives a negative result, the individual may not have that BRCA mutation. They probably have the same risk of BRCA-related cancers as the general population.
• Even if your family history suggests that an inherited predisposition to cancer is likely, genetic tests do not always identify all genetic mutations. In the past, genetic tests largely could not identify missing or rearranged portions of the BRCA1 or BRCA2 genes known to play a role in the development of hereditary breast and ovarian cancers. More recently, the sensitivity of genetic tests has become much better.

What Are the Benefits of Genetic Testing for BRCA1 and BRCA2 Mutations?

• Genetic testing may have benefits regardless of whether a person receives a positive or negative result.
• Potential benefits of a true negative result include a sense of relief about future cancer risk, learning that a person's children are not at risk of inheriting the family's susceptibility to cancer, and the possibility that special checkups, tests, or risk-reducing surgery may not be needed.
• A positive test result may allow people to make informed decisions about their future healthcare, including taking steps to reduce their cancer risk.

Related topic: Psychological Effects of Hereditary Cancer Screening (Genetic Tests)

What Are the Potential Concerns About Genetic Testing for BRCA1 and BRCA2 Mutations?

• The direct medical harms of genetic testing are minimal, but knowing the test results, whether positive or negative, may have harmful effects on a person's emotions, social relationships, finances, and medical choices.
• Coping with the uncertainty of an uninformative negative result or a VUS test result is another potential harm. For this reason, it is important to receive genetic counseling before undergoing genetic testing.
• Genetic test results are normally included in a person's medical records, especially if a doctor or another healthcare provider requested the test or was consulted about the results. For this reason, people considering genetic testing should understand that their test results may become known to other people or organizations with legitimate and legal access to their medical records, such as insurance companies or employers.

Screening for Hereditary Breast and Ovarian Cancer

The aim of screening is to prevent cancer or find the disease at an early stage and increase the chance of treatment. Regular breast cancer screening is strongly recommended for women with BRCA changes. Mammograms, MRG (MRI) scans, ultrasound, breast examinations performed by a doctor, and monthly breast self-examinations are among the many types of screening.

For those with BRCA changes, there is an increased risk of breast cancer among men. Men who carry a mutated BRCA should have regular examinations and mammograms if possible, as well as evaluation of breast lumps.

If you have a family history of cancer, we recommend regular, age-appropriate cancer screening regardless of whether you have undergone genetic testing.

Reducing Your Risk of Developing Hereditary Breast or Ovarian Cancer

Women with BRCA mutations may consider taking medicines that prevent or delay the onset of cancer to help reduce their cancer risk. Examples include tamoksifen and raloxifene, which can reduce breast cancer risk. However, it is unclear whether these drugs reduce breast cancer risk in women with BRCA1 and BRCA2 changes.

Oral contraceptives (birth control pills) may be taken to reduce ovarian cancer risk. However, it remains unclear whether oral contraceptives have an effect on breast cancer risk in BRCA mutation carriers.

Women with BRCA mutations may choose to undergo surgery to reduce their cancer risk. For example, the breasts may be surgically removed to prevent breast cancer, and the ovaries and fallopian tubes may be removed to prevent ovarian cancer. Removing the fallopian tubes and ovaries before age 50 also reduces breast cancer risk.

• Related topic: Why Did Angelina Jolie Have Both Breasts Removed?

Other operations may be performed to help detect cancers early. The earlier the ovaries are removed, the greater the reduction in both breast and ovarian cancer risk. In rare cases, the abdominal wall's lining can develop cancer of the peritoneum after this type of surgery. There is no proven way to screen for peritoneal cancer risk, but studies are underway to see whether CA-125 blood tests after surgery can detect peritoneal cancer.